The present invention relates, in general, to nucleotide mimetics and their derived nucleic acid mimetics, methods for the construction of both and the use of the nucleic acid mimetics in biochemistry and medicine. More particularly, the present invention relates to (i) acyclic nucleotide mimetics, also referred to as acyclic nucleotides, based upon a poly(ether-thioether), poly(ether-sulfoxide) or poly(ether-sulfone) backbone; (ii) a method for synthesizing the acyclic nucleotide mimetics; (iii) acyclic nucleotide mimetic sequences, also referred to as acyclic polynucleotide sequences; (iv) a method for synthesizing the acyclic nucleotide mimetic sequences; and (v) use of the acyclic nucleotide mimetic sequences as oligonucleotides in, for example, antisense applications and procedures.
An antisense oligonucleotide (e.g., antisense oligodeoxyribonucleotide) may bind its target nucleic acid either by Watson-Crick base pairing or Hoogsteen and anti-Hoogsteen base pairing. To this effect see, Thuong and Helene (1993) Sequence specific recognition and modification of double helical DNA by oligonucleotides Angev. Chem. Int. Ed. Engl. 32:666. According to the Watson-Crick base pairing, heterocyclic bases of the antisense oligonucleotide form hydrogen bonds with the heterocyclic bases of target single-stranded nucleic acids (RNA or single-stranded DNA), whereas according to the Hoogsteen base pairing, the heterocyclic bases of the target nucleic acid are double-stranded DNA, wherein a third strand is accommodated in the major groove of the B-form DNA duplex by Hoogsteen and anti-Hoogsteen base pairing to form a triplex structure.
According to both the Watson-Crick and the Hoogsteen base pairing models, antisense oligonucleotides have the potential to regulate gene expression and to disrupt the essential functions of the nucleic acids. Therefore, antisense oligonucleotides have possible uses in modulating a wide range of diseases.
Since the development of effective methods for chemically synthesizing oligonucleotides, these molecules have been extensively used in biochemistry and biological research and have the potential use in medicine, since carefully devised oligonucleotides can be used to control gene expression by regulating levels of transcription, transcripts and/or translation.
Oligodeoxyribonucleotides as long as 100 base pairs (bp) are routinely synthesized by solid phase methods using commercially available, fully automated synthesis machines. The chemical synthesis of oligoribonucleotides, however, is far less routine. Oligoribonucleotides are also much less stable than oligodeoxyribonucleotides, a fact which has contributed to the more prevalent use of oligodeoxyribonucleotides in medical and biological research, directed at, for example, gene therapy or the regulation of transcription or translation levels.
Gene expression involves few distinct and well-regulated steps. The first major step of gene expression involves transcription of a messenger RNA (mRNA) which is an RNA sequence complementary to the antisense (i.e., xe2x88x92) DNA strand, or, in other words, identical in sequence to the DNA sense (i.e., +) strand, composing the gene. In eukaryotes, transcription occurs in the cell nucleus.
The second major step of gene expression involves translation of a protein (e.g., enzymes, structural proteins, secreted proteins, gene expression factors, etc.) in which the mRNA interacts with ribosomal RNA complexes (ribosomes) and amino acid activated transfer RNAs (tRNAs) to direct the synthesis of the protein coded for by the mRNA sequence.
Initiation of transcription requires specific recognition of a promoter DNA sequence located upstream to the coding sequence of a gene by an RNA-synthesizing enzymexe2x80x94RNA polymerase. This recognition is preceded by sequence-specific binding of one or more protein transcription factors to the promoter sequence. Additional proteins, which bind at or close to the promoter sequence, may upregulate transcription and are known as enhancers. Other proteins, which bind to or close to the promoter, but whose binding prohibits action of RNA polymerase, are known as repressors.
There is also evidence that in some cases gene expression is downregulated by endogenous antisense RNA repressors that bind a complementary mRNA transcript and thereby prevent its translation into a functional protein. To this effect see Green et al. (1986) The role of antisense RNA in gene regulation. Ann. Rev. Biochem. 55:569.
Thus, gene expression is typically upregulated by transcription factors and enhancers and downregulated by repressors.
However, in many disease situation gene expression is impaired. In many cases, such as different types of cancer, for various reasons the expression of a specific endogenous or exogenous (e.g., of a pathogen such as a virus) gene is upregulated. Furthermore, in infectious diseases caused by pathogens such as parasites., bacteria or viruses, the disease progression depends on expression of the pathogen genes, this phenomenon may also be considered as far as the patient is concerned as upregulation of exogenous genes.
Most conventional drugs function by interaction with and modulation of one or more targeted endogenous or exogenous proteins, e.g., enzymes. Such drugs, however, typically are not specific for targeted proteins but interact with other proteins as well. Thus, a relatively large dose of drug must be used to effectively modulate a targeted protein.
Typical daily doses of drugs are from 10xe2x88x925-10xe2x88x921 millimoles per kilogram of body weight or 10xe2x88x923-10 millimoles for a 100 kilogram person. If this modulation instead could be effected by interaction with and inactivation of mRNA, a dramatic reduction in the necessary amount of drug could likely be achieved, along with a corresponding reduction in side effects. Further reductions could be effected if such interaction could be rendered site-specific. Given that a functioning gene continually produces mRNA, it would thus be even more advantageous if gene transcription could be arrested in its entirety.
Given these facts, it would be advantageous if gene expression could be arrested or downmodulated at the transcription level.
The ability of chemically synthesizing oligonucleotides and analogs thereof having a selected predetermined sequence offers means for downmodulating gene expression. Three types of gene expression modulation strategies may be considered.
At the transcription level, antisense or sense oligonucleotides or analogs that bind to the genomic DNA by strand displacement or the formation of a triple helix, may prevent transcription. To this effect see, Thuong and Helene (1993) Sequence specific recognition and modification of double helical DNA by oligonucleotides Angev. Chem. Int. Ed. Engl. 32:666.
At the transcript level, antisense oligonucleotides or analogs that bind target mRNA molecules lead to the enzymatic cleavage of the hybrid by intracellular RNase H. To this effect see Dash et al. (1987) Proc. Natl. Acad. Sci. USA, 84:7896. In this case, by hybridizing to the targeted mRNA, the oligonucleotides or oligonucleotide analogs provide a duplex hybrid recognized and destroyed by the RNase H enzyme. Alternatively, such hybrid formation may lead to interference with correct splicing. To this effect see Chiang et al. (1991) Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. J. Biol. Chem. 266:18162. As a result, in both cases, the number of the target mRNA intact transcripts ready for translation is reduced or eliminated.
At the translation level, antisense oligonucleotides or analogs that bind target mRNA molecules prevent, by steric hindrance, binding of essential translation factors (ribosomes), to the target mRNA, as described by Paterson et al. (1977) Proc. Natl. Acad. Sci. USA, 74:4370, a phenomenon known in the art as hybridization arrest, disabling the translation of such mRNAs.
Thus, antisense sequences, which as described hereinabove, may arrest the expression of any endogenous and/or exogenous gene depending on their specific sequence, attracted much attention by scientists and pharmacologists who were devoted at developing the antisense approach into a new pharmacological tool. To this effect see Cohen (1992) Oligonucleotide therapeutics. Trends in Biotechnology, 10:87.
For example, several antisense oligonucleotides have been shown to arrest hematopoietic cell proliferation (Szczylik et al (1991) Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. Science 253:562), growth (Calabretta et al. (1991) Normal and leukemic hematopoietic cell manifest differential sensitivity to inhibitory effects of c-myc antisense oligodeoxynucleotides: an in vitro study relevant to bone marrow purging. Proc. Natl. Acad. Sci. USA 88:2351), entry into the S phase of the cell cycle (Heikhila et al. (1987) A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G(0) to G(1). Nature, 328:445), reduced survival (Reed et al. (1990) Antisense mediated inhibition of BCL2 prooncogene expression and leukemic cell growth and survival: comparison of phosphodiester and phosphorothioate oligodeoxynucleotides. Cancer Res. 50:6565) and prevent receptor mediated responses (Burch and Mahan (1991) Oligodeoxynucleotides antisense to the interleukin I receptor m RNA block the effects of interleukin I in cultured murine and human fibroblasts and in mice. J. Clin. Invest. 88:1190). For use of antisense oligonucleotides as antiviral agents the reader is referred to Agrawal (1992) Antisense oligonucleotides as antiviral agents. TIBTECH 10:152.
For efficient in vivo inhibition of gene expression using antisense oligonucleotides or analogs, the oligonucleotides or analogs must fulfill the following requirements (i) sufficient specificity in binding to the target sequence; (ii) solubility in water; (iii) stability against intra- and extracellular nucleases; (iv) capability of penetration through the cell membrane; and (v) when used to treat an organism, low toxicity.
Unmodified oligonucleotides are impractical for use as antisense sequences since they have short in vivo half-lives, during which they are degraded rapidly by nucleases. Furthermore, they are difficult to prepare in more than milligram quantities. In addition, such oligonucleotides are poor cell membrane penetraters, see, Uhlmann et al. (1990) Chem. Rev. 90:544.
Thus, it is apparent that in order to meet all the above listed requirements, oligonucleotide analogs need to be devised in a suitable manner. Therefore, an extensive search for modified oligonucleotides has been initiated.
For example, problems arising in connection with double-stranded DNA (dsDNA) recognition through triple helix formation have been diminished by a clever xe2x80x9cswitch backxe2x80x9d chemical linking, whereby a sequence of polypurine on one strand is recognized, and by xe2x80x9cswitching backxe2x80x9d, a homopurine sequence on the other strand can be recognized. Also, good helix formation has been obtained by using artificial bases, thereby improving binding conditions with regard to ionic strength and pH.
In addition, in order to improve half-life as well as membrane penetration, a large number of variations in polynucleotide backbones have been done, nevertheless with little success.
Oligonucleotides can be modified either in the base, the sugar or the phosphate moiety. These modifications include the use of methylphosphonates, monothiophosphates, dithiophosphates, phosphoramidates, phosphate esters, bridged phosphorothioates, bridged phosphoramidates, bridged methylenephosphonates, dephospho internucleotide analogs with siloxane bridges, carbonate bridges, carboxymethyl ester bridges, acetamide bridges, carbamate bridges, thioether bridges, sulfoxy bridges, sulfono bridges, various xe2x80x9cplasticxe2x80x9d DNAs, xcex1-anomeric bridges and borane derivatives. For further details the reader is referred to Cook (1991) Medicinal chemistry of antisense oligonucleotidesxe2x80x94future opportunities. Anti-Cancer Drug Design 6:585.
International patent application WO 86/05518 broadly claims a polymeric composition effective to bind to a single-stranded polynucleotide containing a target sequence of bases. The composition is said to comprise non-homopolymeric, substantially stereoregular polymer molecules of the form: 
(SEQ ID NO:1) where:
(a) R1-Rn are recognition moieties selected from purine, purine-like, pyrimidine, and pyrimidine like heterocycles effective to bind by Watson/Crick pairing to corresponding, in-sequence bases in the target sequence;
(b) n is such that the total number of Watson/Crick hydrogen bonds formed between a polymer molecule and target sequence is at least about 15;
(c) Bxcx9cB are backbone moieties joined predominantly by chemically stable, substantially uncharged, predominantly achiral linkages;
(d) the backbone moiety length ranges from 5 to 7 atoms if the backbone moieties have a cyclic structure, and ranges from 4 to 6 atoms if the backbone moieties have an acyclic structure; and
(e) the backbone moieties support the recognition moieties at position which allow Watson-Crick base pairing between the recognition moieties and the corresponding, in-sequence bases of the target sequence.
According to WO 86/05518, the recognition moieties are various natural nucleobases and nucleobase-analogs and the backbone moieties are either cyclic backbone moieties comprising furan or morpholine rings or acyclic backbone moieties of the following forms: 
where E isxe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94. The specification of the application provides general descriptions for the synthesis of subunits, for backbone coupling reactions, and for polymer assembly strategies. Although WO 86/05518 indicates that the claimed polymer compositions can bind target sequences and, as a result, have possible diagnostic and therapeutic applications, the application contains no data relating to the binding capabilities of a claimed polymer.
International patent application WO 86/05519 claims diagnostic reagents and systems that comprise polymers described in WO 86/05518, but attached to a solid support.
International patent application WO 89/12060 claims various building blocks for synthesizing oligonucleotide analogs, as well as oligonucleotide analogs formed by joining such building blocks in a defined sequence. The building blocks may be either xe2x80x9crigidxe2x80x9d (i.e., containing a ring structure) or xe2x80x9cflexiblexe2x80x9d (i.e., lacking a ring structure). In both cases, the building blocks contain a hydroxy group and a mercapto group, through which the building blocks are said to join to form oligonucleotide analogs. The linking moiety in the oligonucleotide analogs is selected from the group consisting of sulfide (xe2x80x94Sxe2x80x94), sulfoxide (xe2x80x94SOxe2x80x94), and sulfone (xe2x80x94SO2xe2x80x94). However, the application provides no data supporting the specific binding of an oligonucleotide analog to a target oligonucleotide.
Nielsen et al. (1991) Science 254:1497, and International patent application WO 92/20702 describe an acyclic oligonucleotide which includes a peptide backbone on which any selected chemical nucleobases or analogs are stringed and serve as coding characters as they do in natural DNA or RNA. These new compounds, known as peptide nucleic acids (PNAs), are not only more stable in cells than their natural counterparts, but also bind natural DNA and RNA 50 to 100 times more tightly than the natural nucleic acids cling to each other. To this effect of PNA heterohybrids see Biotechnology research news (1993) Can DNA mimetics improve on the real thing? Science 262:1647.
PNA oligomers can be synthesized from the four protected monomers containing thymine, cytosine, adenine and guanine by Merrifield solid-phase peptide synthesis. In order to increase solubility in water and to prevent aggregation, a lysine amide group is placed at the C-terminal. However, there are some major drawbacks associated with the PNA approach. One drawback is that, at least in test-tube cultures, PNA molecules do not penetrate through cell membranes, not even to the limited extent natural short DNA and RNA segments do. The second drawback is side effects, which are encountered with toxicity. Because PNAs bind so strongly to target sequences, they lack the specificity of their natural counterparts and end up binding not just to target sequences but also to other strands of DNA, RNA or even proteins, incapacitating the cell in unforeseen ways.
U.S. Pat. No. 5,908,845 to Segev describes nucleic acid mimetics consisting of a polyether backbone, bearing a plurality of ligands, such as nucleobases or analogs thereof, which are able to hybridize to complementary DNA or RNA sequences. More specifically, various building blocks based upon polyether backbone, such as polyethylene glycol (PEG), for synthesizing nucleotide mimetics, as well as oligonucleotide mimetics formed by joining such building blocks in a defined manner, methods for synthesizing both and the use of both in biochemistry and medicine are described. According to U.S. Pat. No. 5,908,845, the oligonucleotide mimetics are of the following optional forms: 
(SEQ ID NOs:2 and 3) where n is an integer greater than one, each of B1-Bn is independently a chemical functionality group, such as, but not limited to, a naturally occurring nucleobase, a nucleobase binding group or a DNA interchelator, each of Y1-Yn is a first linker group, each of X1-Xn is a second linker group, C1-Cn are chiral carbon atoms and [K] and [I] are a first and second exoconjugates.
Although the specification of U.S. Pat. No. 5,908,845 provides general description for the synthesis of the subunits for backbone coupling reactions and for polymer assembly and modifications strategies thereof, U.S. Pat. No. 5,908,845 includes no experimental data as to the feasibility of the synthetic procedure itself. While attempting to synthesize the above polyether nucleic acids, it was realized that synthesis yields are less than sufficient for efficient mass production.
There is thus a widely recognized need for, and it would be highly advantageous to have, oligonucleotide analogs devoid of these drawbacks, and which are characterized by (i) ease of synthetic procedure and proven synthetic efficiency; and which are further characterized by properties common to the above described polyether nucleic acids, such as (ii) sufficient specificity in binding to target sequences; (iii) solubility in water; (iv) stability against intra- and extracellular nucleases; (v) capability of penetrating through cell membranes; and (vi) when used to treat an organism, low toxicity, properties that collectively render an oligonucleotide analog highly suitable as an antisense therapeutic drug.
It is one object of the present invention to provide compounds that bind dsDNA, ssDNA and/or RNA strands to form stable hybrids therewith.
It is a further object of the invention to provide compounds that bind dsDNA, ssDNA and/or RNA strands more strongly then the corresponding DNA, yet less strongly then PNA.
It is another object to provide compounds wherein naturally-occurring nucleobases or other nucleobase-binding moieties or instead of some or all the base(s), a linker arm which terminates with a chemical functionality groups, are covalently bound to a poly(ether-thioether), poly(ether-sulfoxide) or poly(ether-sulfone) backbone.
It is yet another object to provide compounds other than RNA or PNA that can bind under in vivo conditions one strand of a double-stranded polynucleotide, thereby displacing the other strand.
It is yet a further object of the invention to provide a method for fabricating building blocks suitable for the fabrication of such compounds.
It is still a further object of the invention to provide a method for fabricating such compounds from their building blocks.
It is still another object to provide therapeutic and prophylactic methods that employ such compounds.
Additional objectives of the inventions are further described hereinbelow.
According to one aspect of the present invention there is provided a compound comprising a poly(ether-thioether) backbone having a plurality of chiral carbon atoms, the poly(ether-thioether) backbone bearing a plurality of ligands being individually bound to the chiral carbon atoms, the ligands including a moiety selected from the group consisting of a naturally occurring nucleobase and a nucleobase binding group.
According to another aspect of the present invention there is provided a compound comprising a poly(ether-sulfoxide) or a poly(ether-sulfone) backbone having a plurality of chiral carbon atoms, the poly(ether-sulfoxide) or poly(ether-sulfone) backbone bearing a plurality of ligands being individually bound to said chiral carbon atoms, said ligands including a moiety selected from the group consisting of a naturally occurring nucleobase and a nucleobase binding group.
According to further features in preferred embodiments of the invention described below one or more linker arms which terminate with chemical functionality group(s) replace one or more of the naturally occurring nucleobase(s) and/or nucleobase binding group(s).
According to further features in preferred embodiments of the invention described below, the chiral carbon atoms are separated from one another in the backbone by from four to six intervening atoms.
According to another aspect of the present invention there is provided a compound having the formula: 
(SEQ ID NOs:4-6) wherein:
n is an integer greater than one;
each of B1, B2, Bnxe2x88x921 and Bn is a chemical functionality group independently selected from the group consisting of a naturally occurring nucleobase and a nucleobase binding group.
each of Y1, Y2, Ynxe2x88x921 and Yn is a first linker group;
each of X1, X2, Xnxe2x88x921 and Xn is a second linker group;
C1, C2, Cnxe2x88x921 and Cn are chiral carbon atoms; and
[K] and [I] are a first and a second exoconjugates.
According to further features in preferred embodiments of the invention described below, one or more linker arms which terminate with chemical functionality group(s) replace one or more of the naturally occurring nucleobase(s) and/or nucleobase binding group(s).
According to further features in preferred embodiments of the invention described below, each of the Y1-X1, Y2-X2, Ynxe2x88x921xe2x88x92Xnxe2x88x921 and Yn-Xn first-second linker groups is a single bond.
According to still further features in the described preferred embodiments each of the Y1, Y2, Ynxe2x88x921 and Yn first linker groups is independently selected from the group consisting of an alkyl group, a phosphate group, a (C2-C4) alkylene chain, a (C2-C4) substituted alkylene chain and a single bond.
According to still further features in the described preferred embodiments each of the Y1, Y2, Ynxe2x88x921 and Yn first linker groups is independently selected from the group consisting of a methylene group and a C-alkanoyl group which includes an alkyl of k carbons and a carbonyl moiety, whereas k is an integer between 2 and 20.
According to still further features in the described preferred embodiments each of the X1, X2, Xnxe2x88x921 and Xn second linker groups is independently selected from the group consisting of a methylene group, an alkyl group, an amino group, an amido group, a sulfur atom, an oxygen atom, a selenium atom, a C-alkanoyl group, a phosphate derivative group, a carbonyl group and a single bond.
According to still further features in the described preferred embodiments m percents of the chiral carbons are in an S configuration or alternatively an R configuration, wherein m is selected from the group consisting of 90-95%, 96-98%, 99% and greater than 99%.
According to still further features in the described preferred embodiments [K] and [I] are each a polyethylene glycol moiety.
According to still further features in the described preferred embodiments the compound has the formula: 
According to yet another aspect of the present invention there is provided a compound having a formula: 
wherein:
B is a chemical functionality group, selected from the group consisting of a naturally occurring nucleobase, a nucleobase binding group and a chemical functionality group attached via a linker arm;
Y is a first linker group;
X is a second linker group;
C* is a chiral carbon atom;
Z is a first protecting group; and
A is a leaving group;
According to further features in preferred embodiments of the invention described below, the Y-X first-second linker group is a single bond.
According to still further features in the described preferred embodiments the Y first linker group is selected from the group consisting of an alkyl group, a phosphate group, a (C2-C4) alkylene chain, a (C2-C4) substituted alkylene chain and a single bond.
According to still further features in the described preferred embodiments the Y first linker group is selected from the group consisting of a methylene group and a C-alkanoyl group.
According to still further features in the described preferred embodiments the X second linker group is selected from the group consisting of a methylene group, an alkyl group, an amino group, an amido group, a sulfur atom, an oxygen atom, a selenium atom, a C-alkanoyl group, a phosphate derivative group, a carbonyl group and a single bond.
According to still further features in the described preferred embodiments should the nucleobase include an amino group, the amino group is protected by a second protecting group.
According to still further features in the described preferred embodiments the Z protecting group is selected from the group consisting of a dimethoxytrityl group, a trityl group, a monomethoxytrityl group and a silyl group.
According to still further features in the described preferred embodiments the A leaving group is selected from the group consisting of a halide group, a sulfonate group, an ammonium derivative, a radical moiety that could be replaced by SN1 or SN2 mechanisms.
According to still further features in the described preferred embodiments the second protecting group is selected from the group consisting of a methylbenzylether group, a benzamido group, an isobutyramido group, a t-butoxycarbonyl group, a fluorenylmethyloxycarbonyl group and an acid labile group which is not cleaved by reagents that cleave the Z protecting group.
According to still further features in the described preferred embodiments the compound of has the formula: 
According to still another aspect of the present invention there is provided a process of preparing the above described polymeric compound, the process comprising the steps of (a) obtaining monomers each of the monomers having an ether moiety and a thioether moiety, the ether moiety including at least one etheric bond, the thioether moiety including at least one thioetherie bond, each of the monomers further including at least one chiral carbon atom to which a functionality group being linked, the functionality group being selected from the group consisting of a naturally occurring nucleobase and a nucleobase binding group; (b) attaching a first monomer of the monomers to a solid support; and (c) sequentially condensing monomers in a predetermined sequence to the first monomer for obtaining a polymer of condensed monomers and optionally (d) oxidizing sulfide moieties to sulfoxide and/or to sulfone. Alternatively, monomers may be attached through K and/or I moieties to a polymeric chain, such as a polyethylene glycol unit of varying lengths, itself being attached to a solid support. It will be appreciated that steps (b) and (c) above can alternatively be performed in solution rather than on a solid polymeric support. The resulting polymeric product can thereafter be purified by chromatographic methods well known in the art, such as high performance liquid chromatography (HPLC), TLC and the like.
According to an additional aspect of the present invention there is provided a process of sequence specific hybridization comprising the step of contacting a double stranded polynucleotide with the above described polymeric compound, so that the compound binds in a sequence specific manner to one strand of the polynucleotide, thereby displacing the other strand.
According to yet an additional aspect of the present invention there is provided a process of sequence specific hybridization comprising the step of contacting a single-stranded polynucleotide with the above described polymeric compound, so that the compound binds in a sequence specific manner to the polynucleotide.
According to still an additional aspect of the present invention there is provided a process of modulating the expression of a gene in an organism comprising the step of administering to the organism the above described polymeric compound, such that the compound binds in a sequence specific manner DNA or RNA deriving from the gene.
According to further features in preferred embodiments of the invention described below the modulation includes inhibiting transcription of the gene.
According to still further features in the described preferred embodiments the modulation includes inhibiting replication of the gene.
According to still further features in the described preferred embodiments the modulation includes inhibiting translation of the RNA of the gene.
According to a further aspect of the present invention there is provided a process of treating a condition associated with undesired protein production in an organism, the process comprising the step of contacting the organism with an effective amount of the above described polymeric compound, the compound specifically binds with DNA or RNA deriving from a gene controlling the protein production.
According to yet a further aspect of the present invention there is provided a process of inducing degradation of DNA or RNA in cells of an organism, comprising the steps of administering to the organism the above described polymeric compound, the compound specifically binds to the DNA or RNA.
According to still a further aspect of the present invention there is provided a process of killing cells or viruses comprising the step of contacting the cells or viruses with the above described polymeric compound, the compound specifically binds to a portion of the genome or to RNA derived therefrom of the cells or viruses.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising, as an active ingredient, the above described polymeric compound, and at least one pharmaceutically effective carrier, binder, thickener, diluent, buffer, preservative or surface active agent.
The present invention successfully addresses the shortcomings of the presently known configurations by providing an oligonucleotide analog characterized by (i) sufficient specificity in binding its target sequence; (ii) solubility in water; (iii) stability against intra- and extracellular nucleases; (iv) capability of penetrating through the cell membrane; and (v) when used to treat an organism, low toxicity, properties collectively rendering the oligonucleotide analog of the present invention highly suitable as an antisense therapeutic is drug, and, above all being readily sythesizable.